Organisms must process toxic substances in the environment and/or excretory metabolites. In particular, humans must process drugs and the like of a very wide variety of structures. In mammals, organic compounds having such toxicity are excreted primarily via the kidneys and/or the liver. Excretion in the kidneys occurs through filtration in the glomerulus and secretion in the renal tubules. Organic compounds having toxicity are taken up from membrane of the renal tubules cells on the vascular side and excreted from the brush border membrane side of the renal tubules cells (refer to Non-patent Documents 1 to 7). Hepatocytes also absorb organic compounds having toxicity from the sinusoidal capillary and excrete them into the capillary bile duct (refer to Non-patent Documents 1 to 7).
To date, many biochemical or biological studies have revealed that a specific transporter is responsible for the final stage of organic cation (OC) excretion and suggested the existence of an OC transporter which mediates exchange transport of electroneutral protons and OCs (refer to Non-patent Documents 5 to 7). This putative transporter is considered to be a multidrug recognizing excretion transporter since it recognizes a wide variety of OCs, several types of vitamins, or endogenous compounds (for example, choline and dopamine) including cationic chemicals.
The entity of transporters remains unknown so far, and homologues of known kidney transporters have been searched to identify its molecular entity. However, no molecule (protein) showing the intended function has been identified. That is, specifically what molecules exist as transporter proteins responsible for the final stage of organic cations (OC) excretion remains unknown, and identification of specific molecules has been awaited.
The inventors of the present invention considered that a family of proteins having the intended function may be conserved in bacteria to mammals and assumed that an orthologue of a protein which functions as a multidrug efflux pump in bacteria exists in mammals, and this orthologue is responsible for OC excretion in mammals.
Multidrug efflux pumps of bacteria are classified into several groups (for example, major facilitator superfamily [MSF], small multidrug resistance [SMR] family, resistance modulation cell division [RND] family, ATP binding cassette [ABC] family, and multidrug and toxin extrusion [MATE] family) (refer to Non-patent Documents 8 to 10).
The inventors of the present invention searched databases from their unique viewpoints, and, as a result, found out that genes encoding proteins which are likely to be classified into the MATE family proteins exist in mammals (refer to Non-patent Document 11).    [Non-patent Document 1] Pritchard, J. B. and Miller, D. S. (1993) Physiol. Rev.: 73, 765-96    [Non-patent Document 2] Ullrich, K. J. (1994) Biochim. Biophys. Acta: 1197, 45-62    [Non-patent Document 3] Oude Elferink, R. P., et al. (1995) Biochim. Biophys. Acta: 1241, 215-68    [Non-patent Document 4] Koepsell, H. (1998) Annu. Rev. Physiol.: 60, 243-66    [Non-patent Document 5] Inui, K. I. Et al., (2000) Kidney Int.: 58, 944-58    [Non-patent Document 6] Wright, S. H. and Dantzler, W. H. (2004) Physiol. Rev.: 84, 987-1049    [Non-patent Document 7] Koepsell, H. (2004) Trends Pharmacol. Sci.: 25, 375-81    [Non-patent Document 8] Brown, M. H. et al. (1999) Mol. Microbiol.: 31, 394-5    [Non-patent Document 9] Putman, M. et al. (2000) Microbiol. Mol. Biol. Rev.: 64, 672-93    [Non-patent Document 10] Hvorup, R. N. et al. (2003) Eur. J. Biochem.: 270, 799-813    [Non-patent Document 11] Genbank accession number AK001709    [Non-patent Document 12] Ito, W. et al. (1991) Gene: 1002, 67-70    [Non-patent Document 13] Morimoto, R. et al. (2003) J. Neurochem. 84: 382-91    [Non-patent Document 14] Tamai, I. Et al. (1997) FEBS Lett.: 419, 107-11    [Non-patent Document 15] Morita, Y. et al. (1998) Antimicrob. Agents Chemother.: 42, 1778-82    [Non-patent Document 16] Smith, A. C. et al. (1986) Am. J. Med. Genet.: 24, 393-414    [Non-patent Document 17] Bi, W. et al. (2002) Genome Res.: 12, 713-28
The putative amino acid sequence encoded by the gene described in Non-patent Document 11 has a very low sequence homology with the Na+-dependent multidrug efflux transporter NorM of Vibrio bacteria, a prototype of the MATE family, and it is hard to presume that this protein is classified as a MATE family protein.
Furthermore, the MATE family is a group of recently classified-proteins required for acquisition of multidrug resistance, and only some of them are known to excrete H+ or Na+-dependent cationic chemicals in bacteria. That is, not only characteristics of the whole MATE family have not been elucidated yet, but there has been no assay system for identifying a target protein as a MATE family protein in mammals.